Hypertriglyceridemia is the commonest lipid disorder associated with insulin resistance and type 2 diabetes. It is characterized by increased production and decreased clearance of triglyceride (TG)-rich very low-density lipoproteins (VLDL). Hypertriglyceridemia is a major risk factor for the pathogenesis of atherosclerosis and coronary artery disease, but its pathophysiology is poorly understood. Our long-term goal is to understand why insulin resistance causes abnormal VLDL-TG metabolism and results in the development of hypertriglyceridemia in insulin resistant subjects with obesity and type 2 diabetes. Foxol is a transcription factor that plays a key role in mediating insulin action on gene expression. We have shown that Foxol regulates hepatic expression of apolipoprotein C-III (apoC-III) and microsomal triglyceride transfer protein (MTP), two rate-limiting steps in VLDL-TG metabolism. ApoC-III acts to regulate VLDL-TG hydrolysis and clearance, whereas MTP functions to control VLDL assembly and secretion. Both genes are physiologically suppressed by insulin, and are abnormally elevated in response to insulin resistance. We seek to test the hypothesis that the aberrant expression of apoC-III and MTPis due to excessive Foxol activity, resulting from insulin resistance. We propose three specific aims: 1) To determine whether Foxol mediates insulin action on VLDL-TG metabolism in normal and diabetic mice; 2) To determine whether Foxol plays a role in linking insulin resistance to apoC-III overproduction in the pathogenesis of hypertriglyceridemia;3) To elucidate the role of Foxol signaling through MTP in the pathogenesis of hepatic VLDL-TG overproduction in hypertriglyceridemia. To address these specific aims, we will employ gene transfer and transgenic approaches to achieve gain- vs. loss-of-function of Foxol in cultured hepatocytes as well as in livers of mice with impaired insulin action and/or altered TG metabolism. These studies will help define the mechanism of insulin-dependent regulation of MTPand apoC-III production, and elucidate the molecular links between insulin resistance and hypertriglyceridemia.